Browsing by Author "Silva, Sebastian"

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    Contribution of rare coding variants to microcephaly in individuals with neurodevelopmental disorders
    (2025) Yoon, Jihoon G.; Jang, Hyunsoo; Lee, Seungbok; Jang, Se S.; Park, Soojin; Cho, Jaeso; Kim, Minji; Han, Jiye; Yun, Hyounji; Kim, Man J.; Kim, Soo Y.; Kim, Woo J.; Cho, Anna; Lee, Jin S.; Choi, Murim; Fernandez-Jaen, Alberto; Silva, Sebastian; Uribe San Martin, Reinaldo Moises; Cantillano, Christian; Miyake, Noriko; Lim, Byung C.; Ko, Jung M.; Kim, Ki J.; Yoon, Ki-Jun; Chae, Jong-Hee
    Background Microcephaly, characterized by an abnormally small head size, frequently co-occurs with neurodevelopmental disorders (NDDs). While the genetic basis of NDDs has been widely investigated, the contribution of rare coding variants to microcephaly remains poorly understood. Methods We investigated the relationships between head circumference and rare coding variants in 418 individuals with microcephaly, analyzing data from 1050 exomes (312 trios and 106 proband-only samples). Participants were classified into primary microcephaly (PM) and secondary microcephaly (SM) groups, and their clinical and genetic characteristics were systematically assessed. The functional impact of high-priority candidate genes, RTF1 and ASAP2, was further validated using neural progenitor cells (NPCs) and human forebrain organoid models. Results Exome sequencing revealed 142 causative and 12 candidate genes associated with microcephaly. Pathway analyses indicated that PM genes are linked to early phases of brain development, whereas SM genes are more associated with later stages of neuronal maturation. In addition, the PM group had a significantly higher proportion of autosomal recessive disorders and exhibited more severe microcephaly than the SM group. Notably, females displayed greater microcephaly severity than males, primarily attributable to differences in the origin of the allele and inheritance patterns on the X chromosome. Functional experiments using CRISPR-Cas9 knockout in NPCs and brain organoids demonstrated reduced NPC proliferation, supporting the essential role of RTF1 and ASAP2 in brain development. Conclusions This study sheds light on the complex genetic architecture of microcephaly, emphasizing the impact of rare coding variants on brain development and delineating distinct clinical and molecular profiles underlying PM and SM.
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    Do phytoplankton require oxygen to survive? A hypothesis and model synthesis from oxygen minimum zones
    (2023) Wong, Jane C. Y.; Raven, John A.; Aldunate, Montserrat; Silva, Sebastian; Gaitan-Espitia, Juan Diego; Vargas, Cristian A.; Ulloa, Osvaldo; von Dassow, Peter
    It is commonly known that phytoplankton have a pivotal role in marine biogeochemistry and ecosystems as carbon fixers and oxygen producers, but their response to deoxygenation has scarcely been studied. Nonetheless, in the major oceanic oxygen minimum zones (OMZs), all surface phytoplankton groups, regardless of size, disappear and are replaced by unique cyanobacteria lineages below the oxycline. To develop reasonable hypotheses to explain this pattern, we conduct a review of available information on OMZ phytoplankton, and we re-analyze previously published data (flow cytometric and hydrographic) on vertical structure of phytoplankton communities in relation to light and O-2 levels. We also review the physical constraints on O-2 acquisition as well as O-2-dependent metabolisms in phototrophs. These considerations, along with estimates of the photosynthetic capacity of phytoplankton along OMZ depth profiles using published data, suggest that top-down grazing, respiratory demand, and irradiance are insufficient to fully explain the vertical structure observed in the upper, more sunlit portions of OMZs. Photorespiration and water-water cycles are O-2-dependent pathways with low O-2 affinities. Although their metabolic roles are still poorly understood, a hypothetical dependence on such pathways by the phytoplankton adapted to the oxic ocean might explain vertical patterns in OMZs and results of laboratory experiments. This can be represented in a simple model in which the requirement for photorespiration in surface phytoplankton and O-2-inhibition of OMZ lineages reproduces the observed vertical fluorescence profiles and the replacement of phytoplankton adapted to O-2 by lineages restricted to the most O-2-deficient waters. A high O-2 requirement by modern phytoplankton would suggest a positive feedback that intensifies trends in OMZ extent and ocean oxygenation or deoxygenation, both in Earth's past and in response to current climate change.